A molecular hybridization approach for the design of selective aldose reductase (ALR2) inhibitors and exploration of their activities against protein tyrosine phosphatase 1B (PTP1B)

Type II diabetes mellitus is a metabolic disease associated with insulin resistance and high blood glucose levels. Under hyperglycemic conditions the polyol pathway is significantly activated resulting in a series of stress conditions and, finally, in cellular damage. Aldose reductase is the first enzyme of the polyol pathway which is implicated in the onset of long-term diabetic complications. Although many efforts have been focused on developing clinical aldose reductase inhibitors in previous years, they were fruitless due to the poor selectivity profile over the detoxifying aldehyde reductase enzyme. A series of novel benzothiazole-based 4-oxothiazolidin-2-yl-imino acetic acid derivatives has been designed based on our experience from previously reported (Z)-2-(benzo[d]thiazol-2-ylimino)thiazolidin-4-one derivatives. In addition, we followed a molecular hybridization of two well-known aldose reductase inhibitors (zopolrestat and epalrestat) by replacing toxicophore moieties and combining crucial fragments for aldose reductase inhibitory activity as well as selectivity. The most promising compounds in this series (5b and 5d) exhibited potent aldose reductase inhibitory activity with IC50 values of 46 and 67 nM, respectively, and optimal selectivity towards aldehyde reductase. Moreover, inspired by the idea that certain pharmacophoric features of aldose reductase inhibitors overlap with that of protein tyrosine phosphatase 1B inhibitors, we investigated the inhibitory activity of synthesized compounds towards this enzyme. Finally, an extensive docking simulation study was carried out in order to explore the binding modes of examined compounds in the active sites of these enzymes and to interpret the influence of fluorinated moieties in compounds 5b and 5d on their selectivity profiles.